Inhibition of Cyclooxygenase Metabolite Production Attenuates Ischemia-Reperfusion Lung Injury

Ag, Ljungman; Cm, Grum; Gm, Deeb; Sf, Bolling; Ml, Morganroth

doi:10.1164/ajrccm/143.3.610

Cited by 35 publications

(12 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous investigators have suggested that indomethacin attenuates increases in pulmonary microvascular permeability by inhibiting the release of proinflammatory prostanoids, particularly TxA 2 , by the lung (16,39). In the present study, the addition of U-46619 to the perfusate resulted in a small but statistically significant increase in the release of PGE 2 and TxA 2 by the lung.…”

Section: Discussionsupporting

confidence: 53%

Prostaglandins potentiate U-46619-induced pulmonary microvascular dysfunction

Wright¹,

Kim²,

Rogers

et al. 2000

Journal of Applied Physiology

View full text Add to dashboard Cite

.-The induction of cyclooxygenase is an important event in the pathophysiology of acute lung injury. The purpose of this study was to examine the synergistic effects of various cyclooxygenase products (PGE 2 , PGI 2 , PGF 2␣ ) on thromboxane A 2 (TxA 2 )-mediated pulmonary microvascular dysfunction. The lungs of SpragueDawley rats were perfused ex vivo with Krebs-Henseleit buffer containing indomethacin and PGE 2 (5 ϫ 10 Ϫ8 to 1 ϫ 10 Ϫ7 M), PGF 2␣ (7 ϫ 10 Ϫ9 to 5 ϫ 10 Ϫ6 M), or PGI 2 (5 ϫ 10 Ϫ8 to 2 ϫ 10 Ϫ5 M). The TxA 2 -receptor agonist U-46619 (7 ϫ 10 Ϫ8 M) was then added to the perfusate, and then the capillary filtration coefficient (K f ), pulmonary arterial pressure (Ppa), and total pulmonary vascular resistance (RT) were determined. The K f of lungs perfused with U-46619 was twice that of lungs perfused with buffer alone (P ϭ 0.05). The presence of PGE 2 , PGF 2␣ , and PGI 2 within the perfusate of lungs exposed to U-46619 caused 118, 65, and 68% increases in K f , respectively, over that of lungs perfused with U-46619 alone (P Ͻ 0.03). The RT of lungs perfused with PGE 2 ϩ U-46619 was ϳ30% greater than that of lungs exposed to either U-46619 (P Ͻ 0.02) or PGE 2 (P Ͻ 0.01) alone. When paired measurements of RT taken before and then 15 min after the addition of U-46619 were compared, PGI 2 was found to attenuate U-46619-induced increases in RT (P Ͻ 0.01). These data suggest that PGE 2 , PGI 2 , and PGF 2␣ potentiate the effects of TxA 2 -receptor activation on pulmonary microvascular permeability.capillary filtration coefficient; pulmonary vascular resistance; isolated perfused lung model THROMBOXANE A 2 (TxA 2 ) has been incriminated as an important mediator of the pulmonary microvascular dysfunction that characterizes tissue ischemia and reperfusion injury (29), endotoxin exposure (9), and cutaneous thermal injury (14). In these conditions, as well as others, TxA 2 has been shown to cause vasoconstriction and enhanced microvascular permeability. Upregulation of cyclooxygenase is an important event in the generation of TxA 2 during acute inflammatory states. Cyclooxygenase catalyzes the incorporation of molecular oxygen into arachidonic acid, yielding a cyclic endoperoxide (PGG 2 ); subsequent peroxidation yields PGH 2 , the precursor for the synthesis of TxA 2 and PGE 2 , PGI 2 , and PGF 2␣ . In general, each of these cyclooxygenase products is released by the lung in response to a particular inflammatory stimulus, albeit in varying amounts (9,14).Despite their common origin, the physiological effects of these substances on the pulmonary microvasculature are diverse. For example, TxA 2 and PGF 2␣ are constrictors of the pulmonary vasculature in rats, whereas PGI 2 is a potent vasodilator (4, 5). Furthermore, TxA 2 profoundly increases microvascular permeability, whereas the other agents have little, if any, effect by themselves (20, 27). Several investigators have reported that PGE 2 and PGI 2 potentiate the effects of histamine, bradykinin, and interleukin-1 on microvascular permeability (2,34,35). Thi...

show abstract

Section: Discussionsupporting

confidence: 53%

Prostaglandins potentiate U-46619-induced pulmonary microvascular dysfunction

Wright¹,

Kim²,

Rogers

et al. 2000

Journal of Applied Physiology

View full text Add to dashboard Cite

show abstract

“…Nevertheless, the lung damage imposed by ischemia reperfusion could be the concommitant actions of both toxic oxygen products (21) and cyclooxygenase metabolites (23). We conclude that the inhibition of cyclooxygenase product formation and the attenuation of postischemic lung injury by these drugs may, in part, be due to the removal of toxic oxygen metabolites generated during the reperfusion of the lung.…”

Section: Effect On Pulmonary Pressurementioning

confidence: 88%

Amelioration of postischemic reperfusion injury by antiarrhythmic drugs in isolated perfused rat lung.

Das

Misra

1994

Environ Health Perspect

View full text Add to dashboard Cite

Antiarrhythmic drugs, such as lidocaine, quinidine, and procainamide, have been shown to be effective against postischemic reperfusion injury in isolated rat lungs. Rat lungs were perfused at a constant flow with Krebs-Henseilet buffer supplemented with 4% bovine serum albumin and ventilated with air containing 5% CO2. The lungs were subjected to ischemia by stopping perfusion and ventilation for 60 min followed by 30 min of reperfusion. Lung injury was determined by measuring the increase in wet-to-dry lung weight ratio, while pulmonary arterial pressure and peak airway pressure were calculated from the pre-and postischemic differences. Lidocaine, quinidine, and procainamide at doses of 5, 10, and 20 mg/kg body weight, respectively, were found to attenuate the postischemic lung injury significantly (p<0.0001). The formation of cyclooxygenase products, which were elevated during reperfusion, was also significantly (p<0.0001) inhibited by these drugs. Since these antiarrhythmic agents are found to be powerful scavengers of hydroxyl radicals and can prevent membrane lipid peroxidation, these findings suggest that the antioxidant properties of these drugs may, in part, be responsible for protecting the lungs against reperfusion injury. -Environ Health Perspect 102(Suppl 10): 117-122 (1994)

show abstract

“…Previous investigators have reported that pharmacologic inhibition of COX-2 was protective against lung injury [28,29]. However, anti-inflammatory therapies, such as cyclooxygenase inhibition, have not reduced the incidence of acute lung injury in sepsis because of the multiple redundant pathways that can initiate inflammation [11,30].…”

Section: Discussionmentioning

confidence: 99%